Vortioxetine (also known under the name Lu-AA21004 and the tradename Brintellix®) has the chemical name 1-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine, the structure of which is

Recently, the FDA approved vortioxetine for the treatment of adults with major depressive disorder. The finished product is presented as immediate-release film-coated tablet containing 5 to 20 mg of Vortioxetine (as crystalline hydrobromide salt) as the active substance. Vortioxetine exhibits polymorphism and appears in several polymorphs. A method of producing crystalline vortioxetine and several acid addition salts thereof is disclosed in WO 2007/144005 A1.
Nausea is reported to be the most common adverse reaction and its frequency was dose-related (cf. Prescribing Information Brintellix®). According to WO 2011/023194, the amount of adverse events can be lowered, if vortioxetine is not released in the stomach but in the intestine (enteric coated tablets or enteric coated multiparticulate compositions are suggested).
However, the inventors found that these enterically coated, gastro-resistant formulations show highly variable in-vitro release profiles of vortioxetine hydrobromide (i.e. are highly variable in vivo performance), depending on the individual pH in the intestine of the patient. This problem was further investigated by the present inventors, who also realized that there is the risk of dose dumping if vortioxetine hydrobromide is provided in such a prior art formulation.
It has been unexpectedly found by the present inventors that the above disadvantages can be overcome by providing vortioxetine hydrobromide in a matrix formed from at least one polyethylene oxide and optionally one or more further matrix forming polymers.
Based on these findings, the inventors developed pharmaceutical compositions with an advantageous dissolution profile of vortioxetine hydrobromide that enables controlled release of vortioxetine hydrobromide independent of the pH value of the environment, thereby allowing an excellent balance between reduced adverse events and release profile of the vortioxetine hydrobromide upon administration to a patient.
The present invention therefore provides a solid oral pharmaceutical composition comprising vortioxetine hydrobromide in a matrix formed from at least one polyethylene oxide and optionally one or more further matrix forming polymers.
The present invention also provides a process for the preparation of the solid oral pharmaceutical composition comprising vortioxetine hydrobromide in a matrix formed from at least one polyethylene oxide and optionally one or more further matrix forming polymers. The process comprises the steps of forming a blend of vortioxetine hydrobromide and at least one polyethylene oxide and optionally further matrix forming polymers and/or pharmaceutical acceptable excipients, and compressing the blend.
The present invention also provides a solid oral pharmaceutical composition comprising vortioxetine hydrobromide in a matrix formed from at least one polyethylene oxide and optionally one or more further matrix forming polymers for use in the treatment of a disease selected from affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, irritable bowel syndrome, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, attention deficit hyperactivity disorder, melancholia, posttraumatic stress disorder, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse and alcohol and drug abuse.